The goal of this project is to define the regulatory aspects of the human T cell response to alloantigens. There is need for a more precise approach to therapy, based upon promotion of antigen- specific suppressor responses, while inhibiting effector responses which injure graft tissues. Little is known about the antigen specificity of allo-suppressor cells, or the circuitry of cell-cell interactions. Preliminary results with HLA defined reference panel members and MLR-induced suppressor cells demonstrate a weak correlation for specificity of suppression with the known HLA antigens, consistent with the hypothesis that there could be polymorphic regions of Class I and Class II molecules unique for suppressor T cell receptors. An extensive panel of HLA homozygous lymphoblastoid cell lines will be used to explore this hypothesis in detail. There is considerable evidence for a continuing active immune response in successfully grated drug-suppressed patients, but studies to date using classic definitions of CD4 and CD8 populations, those which relate to specific functional programs in antigen and mitogen stimulation will be extensively employed for in vitro manipulations, and in serial analysis in transplant patients. For example, monoclonal antibody 2H4 reacts with an epitope on the leucocyte common antigen (LCA) T200 family of molecules and marks the inducer of suppression within CD4, while the inducers of B cell help or cytotoxic cells are 2H4-. S6F1 marks an epitope found on a subset of LFA-1 molecules present on mature cytotoxic, but not suppressor, cells. The possibility that minor populations of T cells of unusual phenotype may play a role in alloresponses will also be explored. Preliminary study of blood and graft infiltrates from transplanted patients has revealed doubly positive CD4+CD8+ T cells. In addition, T cells bearing gamma-delta antigen receptor heterodimers, instead of the predominant alpha-beta TCR (T3-Ti) are found in increased numbers in blood and grafts of some patients, and can be cloned. Both of these newly appreciated subsets are of unknown function. This project will interact directly with Project 2 on development and molecular studies of monoclonal antibodies, and with in vivo protocols in the primate transplant Project 3.